The coordination of cell division with differentiation is critical for appropriate retinal formation. If this process is disrupted, vision may be compromised, and in some cases, malignant retinoblastoma may form. The Rb family of proteins (Rb, p107, and p130) lies at the heart of the regulatory network that controls proliferation during development and the suppression of tumorigenesis. Based on our preliminary data, we hypothesize that these proteins play distinct roles regulating proliferation and differentiation during mouse retinal development. This hypothesis stands in contrast to the long-standing assumption that Rb and p107 play redundant roles in the murine retina. In humans, we suggest that the complete absence of any role for p107 and a minimal role for p130 in regulating cell cycle exit during retinal development results in a unique susceptibility to early childhood retinal tumors. In Specific Aim 1, we will study the roles played by each Rb family member in regulating retinal progenitor cell proliferation using mutant mice, recombinant retroviral vectors and retinal explant cultures specifically optimized for such studies. Particular attention will be directed toward elucidating redundant vs. compensatory mechanisms among family members. In Specific Aim 2, gain- and loss-of-function studies will be performed to determine the specific requirement of each Rb family member in the specification and differentiation of the seven classes of retinal cell types. Emphasis will be placed on distinguishing changes in retinal development due to proliferation alterations from direct effects on developmental processes. In Specific Aim 3, we will compare our data on retinal development in the mouse to developmental data obtained from normal human and monkey samples, along with human retinoblastoma samples to address the question of human susceptibility to retinal tumors. Specific mechanisms underlying retinoblastoma formation will be tested in experiments designed to faithfully model retinoblastoma in the mouse. These studies bring together an extensive knowledge base and reagents from the fields of cell cycle control and retinal development to address fundamental questions regarding retinal development and disease.